The long-term goals of this program have been to create monoclonal antibody (mAb)-based therapeutic agents for leukemias and selected cancers and to use studies in preclinical models to understand basic principles of immunotherapy and resistance to immunotherapy in order to effectively apply the concepts to other systems and into humans. On this R01, we have developed novel forms of recombinant CDR grafted humanized anti-CD33 mAb's (HUM195) and various cytotoxic antibody constructs, characterized their biology, biochemistry, radiobiology, and radiochemistry. Phase III studies of HUM195 have been successfully completed. P-glycoprotein mediated "immunological resistance" was described. Beta particle and alpha-emitting antibodies were developed, characterized and entered into human clinical trials. Targetable in vivo alpha generators were invented. Little is known about alpha therapy in vivo, and almost nothing is known about the complicated pharmacology and radiobiology of in vivo alpha generators. Initial monkey studies suggest a risk for renal toxicity at large doses of the drug. This fourth competitive grant therefore builds on several aspects of the prior work by proposing continued exploration of alpha particle and nanogenerator therapy. Initial aims are to abrogate the toxicity of daughter alpha emitting atoms produced by in vivo atomic nanogenerators. This will involve (Aim 1) understanding and then altering the pharmacology of the parent generator complexes and (Aim 2) altering the catabolism of daughter elements. Last, we will try to understand the role of cellular geometry, tumor biodistribution, and dose on alpha particle efficacy in model systems in vivo and in vitro (Aim 3). New discoveries will continue to be applied to human clinical problems in clinical trials and to other tumor systems as possible. [unreadable] [unreadable]